The candidate, Thomas W. Sedlak, M.D., Ph.D., is a clinical fellow in the Department of Psychiatry at Johns Hopkins School of Medicine. His long-term career goal is to become an independent research scientist carrying out research on neuroprotective mechanisms that will ameliorate neuropsychiatric disease. To realize this goal, he has developed a mentored research career development plan that provides training in techniques of neuroscience, oxidative stress, molecular imaging and calcium and nitric oxide signaling. Cell death and dysfunction represent a common end-point for a variety of brain disorders and enhancing resistance to the stresses of aging and neurodegenerative conditions represents a long-term goal in improving human health care. The goal of the present proposal is to characterize the cytoprotective functions of the heme oxygenase/biliverdin reductase pathway, which utilizes heme to form bilirubin. Although bilirubin was once thought to be a solely harmful metabolic byproduct, it is increasingly appreciated as a potent antioxidant that abrogates cell death at physiologic concentrations. A number of clinical studies have linked mild increases in serum bilirubin levels with improved outcomes in conditions such as cerebrovascular disease and coronary artery disease. Our long-term objective is to apply the heme oxygenase/biliverdin reductase/bilirubin pathway to models of neuropsychiatric disease. Towards that objective, the goal of the proposed research is to characterize the regulation of this pathway, as well as the cellular components protected by it. Glutathione is well-appreciated as a fundamental cellular protectant, and we hypothesize that bilirubin serves a complementary function. Specifically, bilirubin may preferentially protect cellular lipids whereas glutathione safeguards cell proteins, each sharing duties in safeguarding DNA. In addition, we seek to characterize the manner in which cells regulate this protective pathway, having previously demonstrated that calcium/calmodulin, an important component of neurotransmission, activates heme oxygenase-2, the first step in bilirubin production in the brain. We will now characterize the role of calcium/calmodulin in regulating biliverdin reductase, the second step in bilirubin production. The gaseous messenger, nitric oxide, also plays a vital role in neurotransmission and cell signaling and we will characterize its impact upon biliverdin reductase activity and cytoprotection. Specifically it is hypothesized that nitric oxide targets cysteine residues of biliverdin reductase to increase its enzymatic activity and cellular protective function. Improved understanding of cellular bilirubin production may guide rational design of treatments for neurodegenerative and neuropsychiatric conditions as well as oxidative cellular damage.